A. Angiomyolipomas in Tuberous Sclerosis and Lymphangioleiomyomatosis
Tuberous sclerosis is a rare genetic disease that causes benign tumors to form in a variety of tissues including the brain, kidneys, lungs and skin (U.S. Pat. No. 6,326,483; Gomez, Ann. N.Y. Acad. Sci. 615:1–7 (1991); Kwiatkowski, et al., Arch. Dermatol. 130:348–354 (1994)). Based upon estimates provided by the National Institutes of Health, tuberous sclerosis affects between 25,000 and 40,000 people in the United States and one to two million people worldwide. It is estimated that about one out of every 6,000 newborns has the disorder.
One of the most common problems associated with tuberous sclerosis is the formation of renal angiomyolipomas, benign growths consisting of blood vessels, fatty tissues and muscle cells ((Bjornsson, et al., Am. J. Path. 149:1201–1208 (1996); Cook, et al., J. Med. Genet. 33:480–484 (1996)). These occur in between 55 and 80% of people with tuberous sclerosis and also occur sporadically in the general population (Ewalt, et al., J. Urol. 160:141–145 (1998); Dabora, et al., Am. J. Hum. Genet. 68:64–80 (2001)). Angiomyolipomas may grow large enough to cause pain, kidney failure and bleeding. In some instances, they may cause severe blood loss and a life threatening drop in blood pressure. At present, the only treatments available are surgical removal or embolization.
A high frequency of renal angiomyolipomas has also been reported to occur in lymphangioleiomyomatosis (Bernstein, et al., Am. J. Respir. Crit. Care Med. 152:2138–2143 (1995)), a rare disease characterized by an unusual type of muscle cell that invades the tissue of the lungs. Although these cells are not considered cancerous, they grow uncontrollably and may eventually interfere with the delivery of oxygen to the rest of the body.
Although angiomyolipomas outside of the kidney or liver are rare, they have been reported as present in a wide variety of other tissues including: the colon (Maesawa, et al., Am. J. Gastroenterol. 91:1852–1854 (1996)); heart (Shimizu, et al., Am. J. Surg. Pathol. 18:1164–9 (1994)); lung (Ito, et al., Arch. Pathol. Lab. Med. 122:1023–1025 (1998)); ovary (Anderson, et al., Int. J. Gynecol. Pathol. 21:69–73 (2002)); retroperitoneum (Mogi, et al., J. Gastroenterol. 33:86–90 (1998)); skin (Argenyi, et al., Am. J. Dermatopathol. 13:497–502 (1991)); spermatic cord (Castillenti, et al., J. Urol. 142:1308–1309 (1989)); and uterus (Yaegashi, et al., Pathol. Int. 51:896–901 (2001)).
B. Interferon gamma
Interferons are a family of functionally related proteins synthesized by eukaryotic cells in response to viruses and other stimuli (Cirelli, et al., Clin. Immunother. 5:22–30 (1996); Billiau, Ann. N. Y. Acad. Sci. 856:22–32 (1998); Galli, et al., Ann. Intern. Med. 123:216–224 (1995)). They are classified in three groups (“alpha, beta and gamma”) based upon their antigenicity and biological characteristics. Interferon gamma is produced mainly upon mitogenic induction of lymphocytes and has potent phagocyte-activating effects not seen with other interferon preparations. The human form of gamma interferon has been patented (U.S. Pat. No. 4,727,138) and is presently being marketed under the trade name “ACTIMMUNE®” as a treatment for chronic granulomatous disease and malignant osteopetrosis.